Alternative titles; symbols
HGNC Approved Gene Symbol: POU3F3
SNOMEDCT: 1351837003;
Cytogenetic location: 2q12.1 Genomic coordinates (GRCh38) : 2:104,853,276-104,927,773 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q12.1 | Snijders Blok-Fisher syndrome | 618604 | Autosomal dominant | 3 |
POU3F3 is a member of the class III POU family of transcription factors (see POU3F1; 602479) that are expressed in the central nervous system. The POU domain in these proteins is required for high affinity binding to octamer DNA sequences (summary by Sumiyama et al., 1996).
Using rat class III Pou sequences as probe to screen a human genomic DNA library, Sumiyama et al. (1996) cloned POU3F3. The deduced 500-amino acid protein contains a C-terminal POU-specific domain and POU homeodomain. Several amino acid residues are repeated in the regions outside the POU domain, including alanine, glycine, proline, glutamine, and histidine. POU3F3 shows a high degree of similarity with mouse Brn1.
Activation of Delta genes, such as Delta1 (DLL1; 606582), by proneural factors is an evolutionarily conserved step in neurogenesis that results in activation of Notch (see 190198) signaling and maintenance of an undifferentiated state in a subset of neural progenitors. Castro et al. (2006) showed that activation of mouse Delta1 involved cooperative binding of Mash1 (ASCL1; 100790) and Brn1/Brn2 (POU3F2; 600494) to an evolutionarily conserved motif in the Delta1 gene. They identified the MASH1/BRN-binding motif in several other human, mouse, and rat genes, suggesting that MASH1 and BRN proteins synergistically regulate genes that control multiple aspects of the neurogenic program.
Using quantitative RT-PCR, Guo et al. (2015) determined that expression of a long intergenic noncoding RNA produced by a gene just upstream of POU3F3, linc-POU3F3 (PANTR1; 618169), was significantly higher in WHO grade III/IV glioma tissues than in WHO grade I/II glioma tissues. POU3F3 showed the opposite expression trend, with lower expression in WHO grade III/IV glioma tissues than WHO grade I/II glioma tissues. In glioma cell lines, linc-POU3F3 expression was negatively correlated with POU3F3 mRNA expression, suggesting that linc-POU3F3 may regulate POU3F3. Overexpression of linc-POU3F3 promoted viability and proliferation of glioma cells, whereas knockdown of linc-POU3F3 had the opposite effects.
Sumiyama et al. (1996) determined that the POU3F3 gene is intronless and is GC rich (73.9%) throughout the coding region.
Sumiyama et al. (1998) mapped the POU3F3 gene to chromosome 3p14.2. However, Gross (2020) mapped the POU3F3 gene to chromosome 2q12.1 based on an alignment of the POU3F3 sequence (GenBank AB001835) with the genomic sequence (GRCh38).
Xia et al. (1993) mapped the Brn1 (Pou3f3) gene to mouse chromosome 1.
In 19 patients, ascertained through matchmaking collaborations and exome sequencing studies, with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified heterozygous mutations in the POU3F3 gene (see, e.g., 602480.0001-602480.0006). Mutations occurred de novo in 17 patients, whereas 1 variant was shared by a similarly affected mother and daughter (patients 18 and 19). Mutations occurred throughout the gene, and mutation types included nonsense and frameshift variants, 4 missense variants affecting highly conserved residues in functional domains, and an in-frame deletion of 5 amino acids; none of the mutations were found in the gnomAD database. Functional expression studies of selected variants (4 protein-terminating, 4 missense, and the in-frame deletion) showed that all mutant proteins were expressed, as expected since intronless genes are insensitive to nonsense-mediated decay. The missense variants showed normal cellular localization, whereas the others showed aberrant localization in the cytoplasm, sometimes associated with protein aggregates. In vitro functional expression studies showed that the 4 protein-terminating mutations had severely impaired transcriptional activation function, as measured by luciferase activity. Two missense mutations (R362L, N456S) and the in-frame deletion showed partially impaired transcriptional activity compared to wildtype. In contrast, the R407L variant showed an increase in luciferase activity, whereas the R407G variant (affecting the same codon) was similar to wildtype. A construct containing a conserved transcriptional binding site from FOXP2 (605317) was used in the studies. The mutant proteins had variably impaired dimerization capacity: in general, the truncating proteins had impaired dimerization, whereas the missense variants were able to dimerize. Snijders Blok et al. (2019) concluded that disruptions of POU3F3 function result in a characteristic neurodevelopmental disorder.
In 2 unrelated patients (patients 1 and 2) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.1085G-T transversion (c.1085G-T, NM_006236.2) in the POU3F3 gene, resulting in an arg362-to-leu (R362L) substitution at a highly conserved residue in the third helix of the POU-S domain, which is involved in DNA binding. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro cellular functional expression studies showed that the mutant protein localized normally and had intact dimerization capacity, although transcriptional activity was impaired compared to wildtype. The authors noted that both patients had a severe disorder associated with epilepsy, and that a dominant-negative effect could not be excluded.
In a 6-year-old girl (patient 4) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.1220G-T transversion (c.1220G-T, NM_006236.2) in the POU3F3 gene, resulting in an arg407-to-leu (R407L) substitution at a conserved residue adjacent to the POU-H domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro cellular functional expression studies showed that the mutant protein localized normally and had intact dimerization capacity, and transcriptional activity was increased compared to wildtype, possibly suggesting a gain of function. An unrelated patient with the disorder had a missense variant affecting the same residue (c.1219C-G transversion, resulting in an arg407-to-gly (R407G) substitution), but in functional studies showed that the R407G variant had normal transcriptional activation activity.
In a 3.5-year-old girl (patient 5) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.1367A-G transition (c.1367A-G, NM_006236.2) in the POU3F3 gene, resulting in an asn456-to-ser (N456S) substitution at a conserved residue in the POU-H functional domain, which is involved in DNA binding. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutant protein localized normally and had only slightly impaired dimerization capacity; transcriptional activation activity was impaired compared to wildtype.
In a 6-year-old boy (patient 8) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.196_197delinsT mutation (c.196_197delinsT, NM_006236.2) in the POU3F3 gene, resulting in a frameshift and premature termination (Asp66SerfsTer26). The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutant transcript escaped nonsense-mediated mRNA decay and was expressed with aberrant cellular localization. It had impaired dimerization capacity and transcriptional activation activity compared to wildtype.
In a 24-year-old man (patient 13) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.668C-A transversion (c.668C-A, NM_006236.2) in the POU3F3 gene, resulting in a ser223-to-ter (S223X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutant transcript escaped nonsense-mediated mRNA decay and was expressed with aberrant cellular localization. It had impaired dimerization capacity and transcriptional activation activity compared to wildtype.
In a 12-year-old boy (patient 17) with Snijders Blok-Fisher syndrome (SNIBFIS; 618604), Snijders Blok et al. (2019) identified a de novo heterozygous c.1284C-A transversion (c.1284C-A, NM_006236.2) in the POU3F3 gene, resulting in a cys428-to-ter (C428X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutant transcript escaped nonsense-mediated mRNA decay and was expressed with aberrant cellular localization. It had impaired dimerization capacity and transcriptional activation activity compared to wildtype.
Castro, D. S., Skowronska-Krawczyk, D., Armant, O., Donaldson, I. J., Parras, C., Hunt, C., Critchley, J. A., Nguyen, L., Gossler, A., Gottgens, B., Matter, J.-M., Guillemot, F. Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. Dev. Cell 11: 831-844, 2006. [PubMed: 17141158] [Full Text: https://doi.org/10.1016/j.devcel.2006.10.006]
Gross, M. B. Personal Communication. Baltimore, Md. 1/7/2020.
Guo, H., Wu, L., Yang, Q., Ye, M., Zhu, X. Functional linc-POU3F3 is overexpressed and contributes to tumorigenesis in glioma. Gene 554: 114-119, 2015. [PubMed: 25445282] [Full Text: https://doi.org/10.1016/j.gene.2014.10.038]
Snijders Blok, L. S., Kleefstra, T., Venselaar, H., Maas, S., Kroes, H. Y., Lachmeijer, A. M. A., van Gassen, K. L. I., Firth, H. V., Tomkins, S., Bodek, S., DDD Study, Ounap, K., and 27 others. De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder. Am. J. Hum. Genet. 105: 403-412, 2019. [PubMed: 31303265] [Full Text: https://doi.org/10.1016/j.ajhg.2019.06.007]
Sumiyama, K., Washio-Watanabe, K., Ono, T., Yoshida, M. C., Hayakawa, T., Ueda, S. Human class III POU genes, POU3F1 and POU3F3, map to chromosomes 1p34.1 and 3p14.1. Mammalian Genome 9: 180-181, 1998. [PubMed: 9457692] [Full Text: https://doi.org/10.1007/s003359900721]
Sumiyama, K., Washio-Watanabe, K., Saitou, N., Hayakawa, T., Ueda, S. Class III POU genes: generation of homopolymeric amino acid repeats under GC pressure in mammals. J. Molec. Evol. 43: 170-178, 1996. [PubMed: 8703082] [Full Text: https://doi.org/10.1007/BF02338824]
Xia, Y.-R., Andersen, B., Mehrabian, M., Diep, A. T., Warden, C. H., Mohandas, T., McEvilly, R. J., Rosenfeld, M. G., Lusis, A. J. Chromosomal organization of mammalian POU domain factors. Genomics 18: 126-130, 1993. [PubMed: 8276396] [Full Text: https://doi.org/10.1006/geno.1993.1435]